Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine’s effects on mitochondrial dynamics in cardiomyocytes.
Abstract Atherosclerosis is a complex pathological process involving macrophages, endothelial cells and vascular smooth muscle cells that can lead to ischemic heart disease; however, the mechanisms underlying cell‐to‐cell communication in atherosclerosis are poorly understood. In this study, we focused on the role of exosomal miRNAs in crosstalk between macrophages and endothelial cells and explored the rarely studied molecular mechanisms involved. Our in vitro result showed that macrophage‐derived exosomal miR‐4532 significantly disrupted human umbilical vein endothelial cells (HUVECs) function by targeting SP1 and downstream NF‐κB P65 activation. In turn, increased endothelin‐1 (ET‐1), intercellular cell adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) and decreased endothelial nitric oxide synthase (eNOS) expression in HUVECs increased attraction of macrophages, exacerbating foam cell formation and transfer of exosomal miR‐4532 to HUVECs. MiR‐4532 overexpression significantly promoted endothelial injury and pretreatment with an inhibitor of miR‐4532 or GW4869 (exosome inhibitor) could reverse this injury. In conclusion, our data reveal that exosomes have a critical role in crosstalk between HUVECs and macrophages. Further, exosomal miR‐4532 transferred from macrophages to HUVECs and targeting specificity protein 1 (SP1) may be a novel therapeutic target in patients with atherosclerosis.
Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%–30% of epileptic patients who fail to achieve seizure control with antiepileptic drug (AED) treatment. Although the mechanisms underlying IE are not well understood, it has been hypothesized that multidrug transporters such as P-glycoprotein (P-gp) play a major role in drug efflux at the blood–brain barrier, and may be the underlying factor in the variable responses of patients to AEDs. The main goal of the present review is to show evidence from different areas that support the idea that the overexpression of P-gp is associated with IE. We discuss here evidence from animal studies, pharmacology, clinical cases and genetic studies.
Purpose: The highly morbid condition known as sarcopenia affects middle-aged and elderly people and is characterized by a progressive loss of whole-body muscle mass accelerated by aging. It is also accompanied by a decline in muscle strength and physiological function. These weakening functions manifest as impaired physical movement, increased risk of falls, disability, lower quality of life, and even death. Sarcopenia is progressively emerging as a new public health issue in China with a quickly aging population, making it vital to investigate effective exercise therapies for sarcopenic patients. Methods: Sixty sarcopenic patients (aged 60-75) from a local hospital in northeast China participated in the study. They were randomly divided into a test group and a control group, with 30 patients in each. The test group underwent a 40-minute whole-body vibration training session for 12 weeks, five times a week, while the control group kept regular routines. Data were collected at the end of the experiment, including muscle strength, muscle mass, muscle function, gait speed, berg balance scale (BBS), five sit-to-stand test (FTSST), activities of daily living (ADL), fall risk assessment scale (FRA), and Sarcopenia Quality of Life Scale (SarQoL) scores. Results: The 12-week whole-body vibration training intervention resulted in a significantly higher value of muscular strength, muscle mass, and muscle function among the test group compared to the control group. The former achieved substantially higher SPPB, ADL, FTSST, and BBS scores than the latter (p < 0.01). With much lower FRA scores and significantly better SarQoL ratings compared to baseline, the test group also significantly outperformed the control group in terms of fall risk and quality of life (p < 0.01). Conclusion: With whole-body vibration training, people with sarcopenia can increase their skeletal muscle strength, considerably enhance their motor function, lower their risk of falls and accidents, and generally improve their quality of life. Whole-body vibration training is worthy of therapeutic use since it is both feasible and practical.
Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents; however, its etiology is unknown. In this study, we investigated the association of five polymorphisms in dopaminergic/GABAergic genes with ADHD using polymerase chain reaction-restriction fragment length polymorphism in a group of 54 children with ADHD and 67 healthy controls. The distribution of AA genotype and A allele frequencies of rs5320 in the dopamine beta-hydroxylase gene in ADHD children differed significantly from that in healthy controls; however, no associations were found between four other polymorphisms in dopaminergic/GABAergic genes and ADHD. We also identified the best model consisting of four loci. We conclude that the rs5320 polymorphism may be considered as a genetic risk factor of ADHD, but the other four polymorphisms were not confirmed to be related directly to ADHD. The multilocus of dopaminergic/GABAergic genes acted in combination to affect susceptibility to ADHD in the children studied.
A large number of papers regarding coronavirus disease 2019 (COVID-19) and epilepsy have been published since the declaration of the COVID-19 pandemic. However, there is no bibliometric analysis on these papers. In this study, we aimed to analyze the bibliometric characteristics of these papers, thus identifying the trends and future directions of COVID-19 and epilepsy research.Scientific papers regarding COVID-19 and epilepsy were retrieved through searches of the Web of Science Core Collection database. Title, authors, contributing institute, country, source journal, times cited, and additional information were extracted from each selected paper. Microsoft Excel 2019 and GraphPad Prism 8 were used to analyze the extracted data and export the bar charts and tables whilst VOSviewer software was used to perform and visualize co-authorship analysis and co-occurrence analysis of keywords.A total of 317 papers regarding COVID-19 and epilepsy were included in the final analysis. Epilepsy & Behavior published the largest number of papers (n = 84). J. Helen Cross and Naoto Kuroda were the most prolific authors (n = 13 each). The United States (n = 88) and the University of London (n = 23) were the country and organization with the most contributions, respectively. The strongest authors' collaborations were between Giovanni Assenza and Jacopo Lanzone and between J. Helen Cross and Nathalie Jette. Selected author keywords were organized into seven clusters, and the keywords in clusters 1 and cluster 4 had the largest average appearing year of any clusters.This is the first bibliometric analysis of papers regarding COVID-19 and epilepsy. Our results showed that the United States was the leading country whilst J. Helen Cross was the most influential scholar in COVID-19 and epilepsy research. psychological consequences of COVID-19, and the safety of COVID-19 vaccines for people with epilepsy, are possible areas for future research on COVID-19 and epilepsy.
Objective Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor-encoding gene, core binding factor α1 (CBFA1). Over 90 mutations in CBFA1 gene have been published to date in 500 independent cases of CCD, including missense mutations, deletions, insertions, frameshift, and splice mutations. However, mutational screening of the CBFA1 gene is still far from saturation, and more novel mutations will be identified to enrich the insights into the molecular basis for the pathogenesis of CCD. The aim of this study was to explore the clinical and image features and detect the mutations of CBFA1 gene in two CCD families. Method In this study, the clinical features were investigated in two CCD families, radiological and CT examinations regarding osseous malformation were carried out over the entire body of these patients with CCD. Blood (2 ml) was drawn from all affected individuals, unaffected family members and one hundred unrelated normal controls, Genomic DNA was extracted from whole blood with PureGene DNA extraction kit and PCR was performed with eight pairs of PCR primers for exons 0 to 7 of the CBFA1 gene. The mutations of CBFA1 gene were screened in these two CCD families. Result (1) The clinical features of patients with CCD include delayed closure of fontanelles, frontal bossing, dysplasia of clavicles, late tooth eruption, and other skeletal anomalies. X-ray and CT examination showed the bulging calvarium, patent fontanelles, wide cranial sutures, multiple Wormian bones, dental dysplasia or aplasia of clavicles. (2) Two mutations were identified, one is novel missense mutation (c.1259C > T[p.T420I]) in CBFA1 gene exon 7, other (c.577C > T[p.R193X]) was reported in Chinese cases with CCD for the first time. Conclusion (1) The clinical and image features of patients in two CCD families include delayed closure of fontanelles, frontal bossing, dysplasia of clavicles, late tooth eruption, and other skeletal anomalies. (2) The T420I and R193X mutations of CBFA1 were reported, expanding the spectrum of CBFA1 mutations causing CCD.
The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit. Such crosstalk is thought to involve mechanotransduction, a process whereby the cells sense mechanical cues such as stiffness, and translate these into biochemical signals, which have an impact on the subsequent cellular activities. Bibliometric analysis is a statistical method that involves investigating different aspects (including authors' names and affiliations, article keywords, journals and citations) of large volumes of literature. Despite an increase in mechanotransduction-related research in recent years, there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field.To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint.Literature on mechanotransduction in cancer published from January 1, 1900 to December 31, 2022 was retrieved from the Web of Science Core Collection. Excel and GraphPad software carried out the statistical analysis of the relevant author, journal, organization, and country information. The co-authorship, keyword co-occurrence, and keyword burst analysis were visualized with VOSviewer and CiteSpace.Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times. With 270 articles, the United States is a well-established global leader in this field, and the University of California system, the most productive (n = 36) and influential institution (n = 4705 citations), is the most highly active in collaborating with other organizations. Cancers was the most frequent publisher with the highest H-index. The most productive researcher was Valerie M. Weaver, with 10 publications. The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane, autophagy, piezo1/2, heterogeneity, cancer diagnosis, and post-transcriptional modifications.Mechanotransduction-related cancer research remains a hot topic. The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations. Research group cooperations exist but remain largely domestic, lacking cross-national communications. The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.
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